The following references give reviews of methods of preparing biaryl compounds: Sainsbury, Tetrahedron, vol. 36 (1980), pp. 3327-3359 and Bringman et al., Angew. Chem. Int. Ed. Engl., vol. 29, (1990), 977-991.
In the Meyers oxazoline method to make unsymmetrical biaryl 2-carboxylic acid derivatives, disclosed in Meyers et al, J. Org. Chem., vol. 43 (1978), pp. 1372-1379, the carboxyl group in 2-methoxybenzoic acids is converted into an oxazoline to activate the 2-methoxy group for nucleophilic substitution by arylmagnesium halide or aryllithium reagent and to protect the carboxyl group in a form that is not subject to nucleophilic attack by the aryl carbanion species.
Carini et al., J. Med. Chem., vol. 34 (1991), 2525-2547 disclose the application of the Meyers oxazoline method to the preparation of 2-(4'-methylphenyl)benzonitrile by the following steps: 1) 2-methoxybenzoic acid is reacted with thionyl chloride; 2) the acyl chloride formed is treated with 2-amino-2-methyl-1-propanol, which provides an amide in the crude form; 3) this amide is subjected to the action of thionyl chloride, forming 4,4-dimethyl-2-(2-methoxyphenyl)-oxazoline (yield 88% from the acid chloride); 4) this oxazoline derivative is reacted with p-tolyl-magnesium bromide and the complex formed is hydrolyzed, which gives 4,4-dimethyl-2-(4'-methylbiphenyl-2'-yl)-oxazoline (yield 91%); and 5) the oxazoline derivative formed is then treated with phosphorus oxychloride, which finally provides 2-(4'-methylphenyl)benzonitrile (yield 96%). The overall yield is 77% but this process has the disadvantage of requiring the use of 5 steps, starting from commercially available products, due to the prior formation of the dimethyloxazolinyl group and its subsequent conversion to the cyano group. U.S. Pat. No. 5,128,355 (to Carini et al.) similarly exemplifies the application of the multistep Meyers oxazoline method to the preparation of 2-(4'-methylphenyl)benzoic acid (example 85), and the conversion of this benzoic acid to the benzonitrile Example 89). Implicitly, these references illustrate that when an aryl magnesium reagent (in this case, p-tolyl magnesium bromide) is used directly to provide the aryl group in an arylbenzonitrile (in this case, 2-(4'-methyl-phenyl)benzonitrile) the nitrile group cannot be present in the substrate that is treated with the aryl magnesium reagent. It must be in a protected precursor form during the coupling process (in this case, as the dimethyloxazolinyl group).
Tamao et al., Bull. Chem. Soc. Japan, vol. 49 (1976), pp. 1958-1969, discloses that arylbromides can be reacted with arylmagnesium halides (aryl Grignard reagents) in the presence of dihalodiphophinenickel complexes to give biaryl compounds. A sole disclosed attempt to react an aryl chloride (chlorobenzene) with an arylmagnesium halide (mesityl) was reported to give only a 6% yield of the desired biaryl. Similar reactions of the bromobenzene with mesitylmagnesium bromide gave yields of 78-96%. This reference states, "The most serious limitation is that the substituents on the organic halides and on the Grignard reagents are restricted to those which cannot react with Grignard reagents."
In a review article titled "Transformations of Chloroarenes, Catalyzed by Transition-Metal Complexes", Chem. Rev., vol 94 (1994), pp. 1047-1062, Grushin et al. state, "Unfortunately, the most reactive iodo- and bromoarenes are the most expensive ones, whereas aryl fluorides are both costly and unreactive. Chloroarenes are certainly the most attractive aryl halides for synthetic applications on an industrial scale, because they are inexpensive and readily available in bulk quantities. The main drawback here is the exceedingly high stability of the aromatic carbon-chlorine bond whose inertness remains the major obstacle on the way to wide utilization of chloroarenes."
Clough et al., J. Org. Chem., vol. 41 (1976), pp. 2252-2255 discloses that 1,8-dihalonapthalenes can be reacted with arylmagnesium halides in the presence of certain soluble nickel catalysts to give 1,8-diarylnaphthalenes. The reactivities of the 1,8-dihalonaphthalenes in this system was found to be I&gt;Br&gt;&gt;Cl.
U.S. Pat. No. 4,912,276 discloses that aryl chlorides can be reacted with arylmagnesium halides in the presence of a nickel-triorganophosphine catalyst to give biaryl compounds. The disclosed scope of the aryl groups in the arylchlorides, the arylmagnesium reagents, and the biaryl compounds consists of phenyl and substituted phenyl with hydrocarbyl or hydrocarbyloxy substituents or protected carbonyl-containing derivatives thereof. These are all substituents that are unreactive to arylmagnesium halides. The only biaryl whose preparation is exemplified by working examples is the symmetrical biaryl 2,2'dimethylbiphenyl, prepared from 2-chlorotoluene and o-tolylmagnesium chloride (derived from 2-chlorotoluene).
Pridgen, J. Org. Chem., vol. 47 (1982), pp. 4319-4323 discloses two examples in which 2-(chlorophenyl)-2-oxazolines are reacted with arylmagnesium halides in the presence of a diphosphine-chelated nickel catalyst to give the corresponding 2-(biaryl)-2-oxazoline compounds. The oxazoline group activates the aryl chloride and provides a form of the carboxyl group that is protected from reaction with the arylmagnesium halide.
U.S. Pat. No. 5,288,895 discloses a process for the preparation of 4-methyl-2'-cyanobiphenyl (a.k.a. 2-(4'-methylphenyl)benzonitrile) wherein a 2-halobenzonitrile is reacted with a 4-methylphenyl magnesium halide in the presence of manganous salt. The Examples of this patent, which describe reactions of 2-chlorobenzonitrile, report analyzed chemical yields of 60-75% of 2-(4'-methylphenyl)benzonitrile) in a recovered "brown viscous liquid". Recrystallizations (plural) give the product as a beige solid, but the yields of these purified solids are not reported.
This patent also discloses tests showing that the direct reaction of 4-methylphenyl magnesium bromide with 2-chlorobenzonitrile, in the absence of manganese salt, "proves incapable of giving 4-methyl-2'-cyanobiphenyl". Analysis showed unreacted 2-chlorobenzonitrile and the addition product of the reagent to the nitrile group, 2-chloro-1-phenyl(4-tolyl)ketone, but no trace of 2-(4'-methylphenyl)benzonitrile.
This patent also discloses attempted reactions of several equivalents of 4-methylphenyl magnesium bromide with 1 equivalent of 2-bromobenzonitrile and 0.3 equivalents of either PdCl.sub.2 or NiCl.sub.2 in tetrahydrofuran at 0.degree. C. Yields of 22% and 27%, respectively, of 2-(4'-methylphenyl)benzonitrile were analyzed in recovered crude residue. Similar reactions with 0.003 equivalents tetrakis(triphenylphosphine)palladium(0) at 0 and 65.degree. C. gave only a 1% yield in the residue.
Negishi et al, J. Org. Chem., vol. 42 (1977), pp. 1821-1823 discloses reactions of arylzinc derivatives (arylzinc chloride or diarylzinc) with aryl bromides or iodides in the presence of nickel or palladium complexes as catalysts to produce unsymmetrical biaryls. The arylzinc derivatives were prepared by a metathesis reaction between the corresponding aryllithium and zinc dichloride. The reference does not report any attempt to react an arylzinc derivative with an aryl chloride and is silent as to whether aryl chlorides are suitable or unsuitable as alternatives to the aryl bromides or iodides. The authors comment on the ability of arylzinc derivatives to tolerate various electrophilic functional groups, such as nitrile and ester, in the arylbromide or iodide.
Zhu et al., J. Org. Chem., vol. 56 (1991), pp. 1445-1453 similarly discloses reactions of arylzinc halides with aryl bromides or aryl iodides in the presence of a palladium tetrakis(triphenylphosphine as catalyst to form biaryl compounds. The arylzinc halides were prepared by the reaction of the arylhalide with a form of highly reactive zinc.
Silbille et al., J. Chem. Soc. Chem. Comm., 1992, pp. 283-284 discloses a reaction of 4-trifluoromethylphenylzinc chloride, prepared from 4-trifluoromethylchlorobenzene, with 4-bromobenzonitrile using the palladium complex PdCl.sub.2 (PPh).sub.3).sub.2 as catalyst to form 4-trifluoromethylphenyl-4'-cyanobiphenyl. This reference also discloses a method of preparing arylzinc halides from arylchlorides and arylbromides, including ones bearing various functional groups such as ester, nitrile, or ketone.
Carini et al., J. Med. Chem., vol. 34 (1991), 2525-2547, cited above, discloses the preparation of 3-(4'-methylphenyl)benzonitrile by reacting 4-methylphenylzinc halide (prepared from 4-bromotoluene via 4-methylphenylmagnesium bromide, which is reacted with zinc chloride) and 3-bromobenzonitrile in the presence of bis(triphenylphosphine)nickel dichloride as precatalyst. U.S. Pat. No. 5,128,355 (to Carini et al.) similarly shows an equation (Scheme 14, Equation e) representing the nickel catalyzed cross coupling of a methylphenyizinc chloride (isomer unspecified) with a bromobenzonitrile (isomer unspecified) to give a methylphenylbenzonitrile (isomer unspecified). This method is exemplified only for the preparation of 2,6-dicyano-4'-methylbiphenyl from 2,6-dicyanophenylbromide (Example 343).
Mantlo et al., J. Med. Chem., vol. 34 (1991), pp. 2919-2922 discloses the preparation of 2-(4'-methylphenyl)benzonitrile from 4-bromotoluene and 2-bromobenzonitrile according to the method (referenced) of Negishi et al. J. Org. Chem., vol. 42 (1977), pp. 1821-1823. A zinc derivative was formed from the 4-bromotoluene and reacted with the 2-bromobenzonitrile in the presence of a catalytic amount of a dichlorobis(triphenylphosphine)nickel.
European Patent Application 470,794 discloses a process for preparing biphenylcarbonitriles in which a metal or organometallic 4-methylphenyl derivative is reacted with a bromo-, iodo-, or trifluoromethanesulphonyloxybenzonitrile in the presence of a palladium or nickel catalyst. The metal or organometallic 4-methylphenyl derivatives disclosed are of copper, lithium, tin, silicon, zirconium, aluminum, thallium, mercury, and magnesium. (Zinc is nowhere mentioned.) 4-methylphenyl derivatives of tributyltin are particularly preferred and are the only 4-methylphenyl derivatives shown by working example.
Only two of the working examples relate to the disclosed process for preparing biphenylcarbonitriles, Examples 1 and 2. Both involve reactions of the 4-methylphenyl tributyltin derivative with 2-bromobenzonitrile in the presence of tetrakis(triphenylphosphine)palladium. The 4-methylphenyl tributyltin derivatives are prepared by the reaction of the corresponding 4-methylphenyl magnesium bromide with tributyltin chloride, followed by separation and high vacuum distillation of the 4-methylphenyl tributyltin derivative. Example 2 shows the preparation of 4'-methylbiphenyl-2-carbonitrile (a.k.a. 2-(4'-methylphenyl)benzonitrile) by this method, involving a prolonged reaction time (36 hours) for the coupling reaction.
Percec et al. J. Org. Chem., vol. 60 (1995), pp. 6895-6903 discloses reactions in which certain aryl mesylates are reacted with 1.8-2.0 equiv. of certain arylmagnesium halide or arylzinc halide reagents in the presence of 1.0 equiv. of zinc powder and a nickel phosphine complex as catalyst to form unsymmetrical biaryls in yields ranging from 31-60%.
Zembayashi et al., Tetrahedon Letters, vol 47 (1977), pp. 4089-4092 discloses reductive coupling of aryl bromides to the corresponding symmetrical biaryls by zinc powder in the presence of a nickel-phosphine complex as catalyst. The reference states, "Although the exact mechanism of the present coupling reaction has not yet been clarified, it seems likely that organozinc intermediates are not involved, but metallic zinc acts as a reducing agent for the Ni(II) species as mentioned above."
Colon et al., J. Org. Chem., vol. 51 (1986), pp. 2627-2637 and U.S. Pat. No. 4,263,466 (to Colon et al.) similarly discloses reductive coupling of aryl chlorides to the corresponding symmetrical biaryls by an excess of a reducing metal (Zn, Mg, or Mn) in the presence of a catalyst formed from an anhydrous nickel salt and triphenylphosphine. In an extensive exposition on the mechanism of the reaction, the authors conclude that the reducing metal serves to reduce the nickel salt and various arylnickel intermediates participating in the reaction. Nowhere do the authors make any mention of an arylzinc intermediate.
Kageyama et al., Synlett, 1994, pp. 371-2 discloses a procedure said to be advantageous "compared to the original Colon's method" (the reference discussed in the preceding paragraph herein) in which pyridine is used as solvent for the reductive coupling reaction affording symmetrical biaryls. This reference further discloses the extension of this procedure to reductive cross-coupling reactions of certain aryl halides (1 equiv.) in the presence of zinc powder (2 equiv.) and a nickel-phosphine catalyst in pyridine solvent to provide unsymmetrical biaryls. This reference is mainly concerned with the preparation of 4'-methylbiphenyl-2-carbonitrile-(also known as 2-(4'-methylphenyl)benzonitrile) by such reaction of 4-bromotoluene and 2-chlorobenzonitrile, which is reported to provide the desired unsymmetrical (cross-coupled) biaryl product in 69% yield. The two undesired symmetrical (homo-coupled) biaryl byproducts are formed in 11-12% yield each. Attempted reaction of 3-chlorotoluene with 2-chlorobenzonitrile did not afford the desired cross-coupled product, nor any homocoupled bitolyl. Only a 21% yield of the homocoupled bisbenzonitrile) is reported. There is no indication in the reference that the 4-chlorotoluene reacted at all.
A frequently used method of synthesizing biaryls containing electrophilic functional groups on a laboratory scale is the palladium catalyzed cross-coupling (Suzuki coupling), in which iodoaromatics, bromoaromatics, or aryl sulfonates are reacted with arylboronic acids or boronate esters in the presence of palladium catalysts and a base. An early report of this general reaction is Miyaura et al., Synthetic Communications vol. 11 (1981), 513. In this reference, chlorobenzene is reported to fail to react with phenylboronic acid using tetrakis(triphenylphosphine)palladium as catalyst in this system.
Ali et al., Tetrahedron, vol 48 (1992), pp. 8117-8126 discloses Suzuki-type cross-coupling reactions of arylboronic acids with pi-electron deficient heteroaryl chlorides (chloropyridines, chloropyrimidines, and chloropyrazines, chloroquinolines). These authors state, "It is widely accepted that palladium-catalyzed cross coupling reactions of arylboronic acids, and indeed of other organometallic species, proceed best with aryl or heteroaryl bromides or iodides, and either poorly, or more commonly, not at all with the corresponding chlorides." These investigators confirmed early literature reports that reaction of phenylboronic acid with either chlorobenzene or 3-chloropyridine in the presence of tetrakis(triphenylphosphine) palladium failed to produce any coupled product. Using Pd(bis-1,4-(diphenylphosphino)butane)Cl.sub.2, however, they were able to get chlorobenzene to react to give 28% of biphenyl, and 3-chloropyridine was converted to 3-phenylpyridine in 71% yield. Among 2-chloropyridines, the reaction tolerated some (3-nitro, 5-chloro) but not other (3-OH, 3-CONH.sub.2) substituents.
U.S. Pat. No. 5,130,439 discloses a process for preparing certain protected tetrazolyl biphenyls in which a protected tetrazolylphenylboronic acid or boronate derivative is reacted with a substituted phenyl bromide or iodide or a substituted sulfonyloxyphenyl derivative in the presence a base and a nickel, palladium or platinum catalyst, preferably palladium. Three of the working examples (Examples 4, 9, and 12) relate to the disclosed process for preparing the protected tetrazolyl biphenyls, and all involve reactions of triphenylmethyltetrazolylphenylboronic acid with a substituted (4-methyl, 4-hydroxymethyl, 4-formyl) bromobenzene in the presence of a tetrakis(triphenylphosphine)palladium catalyst and a carbonate base. This process has the disadvantage of requiring prior synthesis of the triphenylmethyltetrazolylphenylboronic acid This reference discloses a process for preparing the triphenylmethyltetrazolylphenylboronic acid from the corresponding bromobenzonitrile by reacting it with tributyltin chloride and sodium azide, then with triphenylmethyl chloride to form the triphenylmethyltetrazolylphenylbromide, which is reacted sequentially with n-butyllithium and triisopropylborate and the resulting boronate ester is finally hydrolyzed to the boronic acid. This reference illustrates that the nitrile group must be protected, in this case as the triphenylmethyltetrazolyl group, to be compatible with the use of an aryllithium intermediate in the overall process.
European Patent Application 470,795 discloses a process for preparing biphenylcarbonitriles in which a 4-methylphenyl boronic acid or boronate ester is reacted with a bromo-, iodo-, or trifiuoromethanesulphonyloxy-benzonitrile in the presence of a palladium or nickel catalyst and a suitable base. Three of the working examples Examples 1, 2, and 6) relate to the disclosed process for preparing biphenylcarbonitriles, and all involve reactions of the 4-methylphenylboronic acid with 2-bromobenzonitrile in the presence of a palladium catalyst and sodium carbonate.
Saito et al., Tetrahedron Letters, vol 37 (1996), pp. 2993-2996 states, "The palladium-catalyzed cross-coupling reaction of arylboronic acids with aryl halides or triflates gives biaryls. High yields have been achieved with many substrates having various functional groups on either coupling partner, when using aryl bromides, iodides, or triflates as an electrophile. Chloroarenes are an economical and easily available, but they have been rarely used for the palladium catalyzed cross coupling reaction of arylboronic acids because of the oxidative addition of chloroarenes is too slow to develop the catalytic cycle. However, chloroarenes have been an efficient substrate for the nickel catalyzed cross coupling reaction with Grignard reagents . . . developed by Kumada and Tamao." This reference (Saito et al.) discloses syntheses of unsymmetrical biaryls by a nickel(0) catalyzed reaction of arylchlorides with arylboronic acids and tripotassium phosphate as the base at elevated temperatures.
U.S. Pat. No. 5,559,277 discloses a process for preparing biaryls by the Suzuki reaction of haloaromatics or arylsulfonates with arylboronates in the presence of a base and certain specific palladium compounds as catalysts. In addition to numerous bromoaromatics, reactions of chloroacetophenone and 2-chlorobenzonitrile are shown in working examples. All the working examples use at least 50% mole excess of the arylboronate relative to the haloaromatic and conduct the reaction for 16 hours at 130.degree. C. The disclosed process also has the disadvantage of requiring the separate preparation of the arylboronate. Example 7 describes the preparation of 2-cyano-4-methylbiphenyl (a.k.a. 2-(4'-methylphenyl)benzonitrile) from 2-chlorobenzonitrile and 4-methylphenylboronic acid in 73% yield (49% yield on the 4-methylphenylboronic acid).
Kalinin, Synthesis, 1992, 413-432 reviews carbon-carbon bond formation to heteroaromatics using nickel and palladium catalyzed reactions. It shows numerous examples of the formation of unsymmetrical biaryls, wherein at least one of the aryl groups includes a heteroatom, including examples of palladium catalyzed reactions of arylbromides and aryliodides with arylzinc halides, palladium catalyzed reactions of chloropyridines with arylmagnesium halides, and nickel catalyzed reactions of arylchlorides and arylbromides with arylmagnesium halides. Nowhere does it show any example of a formation of an unsymmetrical biaryl by a reaction of an arylchloride with an arylzinc derivative.
U.S. Pat. No. 5,364,943 discloses the preparation of 3-amino-2-phenylpyridine and two 3-(substituted benzylamino)-2-phenylpyridine derivatives by the reaction of the corresponding 3-amino-2-chloropyridine or N-benzyl derivative with phenyl magnesium bromide in the presence of bis(phosphine)nickel dichloride complexes. For the parent compound (Example 7), a total of 4.4 eq. of phenylmagnesium bromide was reacted with 3-amino-2-chloropyridine and 0.5 eq. [bis(diphenylphosphino)ethane] nickel(II) chloride over the course of two days, to ultimately obtain a 48% of the isolated product.